Objective-Inflammation plays an integral role in the development of abdominal aortic aneurysms (AAAs), and the expression of cyclooxygenase (COX)-2 is increased in aneurysmal tissue compared with normal aorta. Nonsteroidal anti-inflammatory drugs, which inhibit the activity of COX-1 and COX-2, decrease AAA expansion in humans and animal models of the disease. In the current study, we investigated the effectiveness of selective inhibition of COX-1 or COX-2 in attenuating AAA formation. Methods and Results-Eight-week-old male apolipoprotein E-deficient mice were treated with selective inhibitors of COX-1 or COX-2, SC-560 (Ϸ25 mg ⅐ kg Ϫ1 ⅐ day Ϫ1), or celecoxib (Ϸ125 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 ), respectively. COX inhibitors were administered 1 week before angiotensin II (Ang II; 1000 ng ⅐ kg Ϫ1 ⅐ min Ϫ1 ) or saline infusion and throughout the time course of the experiment. COX-1 inhibition had no effect on incidence (control: 90% [9:10] versus ) or severity of Ang II-induced AAA formation. In contrast, celecoxib decreased the incidence (control: 74% Key Words: cyclooxygenase-1 Ⅲ cyclooxygenase-2 Ⅲ abdominal aortic aneurysms Ⅲ celecoxib Ⅲ prostaglandin E 2 A bdominal aortic aneurysms (AAAs) are an increasing health concern, particularly in the male population Ͼ65 years of age. AAAs are a permanent dilation of the artery leading to extensive remodeling of the vessel wall with a potential for rupture and resulting mortality. Hallmarks of AAAs are proteolytic degradation and the presence of an inflammatory infiltrate within the vascular wall. 1 Inflammatory cells within the vascular wall are a significant source of proteolytic enzymes that contribute to the disease. 1,2 Thus, a putative cause of human AAAs may be cellular remodeling within the vascular wall resulting from chronic inflammation and matrix degradation. See page 956Prostanoids are a class of inflammatory mediators that are dramatically increased in aneurysmal tissue. [3][4][5] Prostanoids, which include prostaglandins and thromboxane A 2 , are synthesized by the 2 known isoforms of prostaglandin G/H synthase, also known as cyclooxygenase (COX)-1 and COX-2. 6 -8 COX-1 is constitutively expressed in most tissues, whereas COX-2 expression is inducible and is primarily responsible for the synthesis of prostanoids that contribute to inflammation. 6 -8 COX-2 expression is induced during the development of aneurysms, whereas, COX-1 expression is not altered, suggesting a primary role for COX-2 in the development of this disease. [3][4][5] Although a variety of inflammatory cells are present in aneurysmal tissue, macrophages are believed to have a pronounced role in the pathogenesis of AAAs. 2,9,10 Activated macrophages within the inflammatory infiltrate of human AAAs are a significant source of COX-2 expression, which may be responsible for the synthesis of prostanoids contributing to the vascular inflammation. 4,5 The prostanoid most often observed in human aneurysmal tissue is prostaglandin E 2 (PGE 2 ). 4,5 PGE 2 synthesized by macrophages and smooth muscle cells (S...

Our findings suggest that increased COX-2 expression in smooth muscle cells of the abdominal aorta contributes to AAA formation in mice by enhancing inflammatory cell infiltration.

Rho kinases (ROCKs) are serine-threonine protein kinases that regulate the actin cytoskeleton. Recent studies suggest that ROCKs also play an important role in cardiovascular disease. However, the isoform- and tissue-specific role of ROCKs in mediating this process is unknown. Using homologous recombination, we generated mutant mice harboring alleles with homozygous deletion of ROCK1 (ROCK1(-/-)). Most ROCK1(-/-) mice die perinatally. However, a few ROCK1(-/-) mice survive to adulthood, are phenotypically normal, and have no apparent compensatory changes in ROCK2. Using these ROCK1(-/-) mice, we show that ROCK1 in bone marrow-derived macrophages is critical to the development of atherosclerosis, in part, by mediating foam cell formation and macrophage chemotaxis. Lipid accumulation and atherosclerotic lesions were reduced in atherosclerosis-prone LDLR(-/-) mice, whose bone marrows have been replaced with bone marrows derived from ROCK1(-/-) mice. Bone marrow-derived ROCK1-deficient macrophages exhibited impaired chemotaxis to monocyte chemotactic protein-1 and showed reduced ability to take up lipids and to develop into foam cells when exposed to modified low-density lipoprotein. These findings indicate that ROCK1 in bone marrow-derived cells is a critical mediator of atherogenesis and suggest that macrophage ROCK1 may be an important therapeutic target for vascular inflammation and atherosclerosis.

The inhibition of COX-2-derived PGE(2) may enhance P. gingivalis LPS-induced atherosclerosis by increasing macrophage production of TNFalpha.

1 Adenosine 5'-triphosphate (ATP) has important roles in the cardiovascular system, modulating vascular tone by acting as both a vasoconstrictor and a vasodilator. 2 The dilator function of ATP is traditionally thought to be monophasic and mediated primarily by nitric oxide (NO). 3 Here we have identi®ed the endothelium-dependent biphasic nature of ATP-induced vasodilatation of the rat isolated mesenteric bed and investigated the two distinct pathways involved. 5 At doses upwards of 1610 78 moles (1610 78 ± 3610 77 moles), ATP also induced prolonged vasodilatations which were unaltered by L-NAME, L-NAME (1610 73 M) and indomethacin (1610 75 M), or by ODQ, but were abolished in the presence of KCl. 6 In addition, the cannabinoid CB 1 receptor antagonist SR141716A (1610 75 M) was found to inhibit the second prolonged phase of vasodilatation. However, at the concentration used SR141716A is reported to be non-selective. A second CB 1 receptor antagonist, AM251 (1610 76 M), had a small but signi®cant inhibitory eect on the second phase of ATP-induced vasodilatation. SR141716A, AM251 and KCl (6610 72 ± 1.2610 71 M) all inhibited anandamideinduced relaxation of the isolated mesenteric bed. 7 These observations demonstrate that ATP stimulates vasodilatation of the mesenteric bed by two distinct mechanisms involving the release of NO and an EDHF. In the absence of better pharmacological tools we can only speculate as to the involvement of an endogenous CB 1 receptor ligand in these responses.

Abdominal aortic aneurysms (AAAs) are a chronic condition that often progress over years to produce a weakened aorta with increased susceptibility for rupture, and currently, there are no pharmacological treatments available to slow disease progression. AAA development has been characterized by increased expression of cyclooxygenase-2 (COX-2), and inactivation of COX-2 before disease initiation reduces AAA incidence in a mouse model of the disease. The current study determined the effectiveness of COX-2 inhibition on AAA progression when treatment was begun after initiation of the disease. COX-2 inhibitor treatment with celecoxib was initiated after angiotensin II-induced AAA formation in a strain of nonhyperlipidemic mice that we have previously identified as highly susceptible to AAA development. When analyzed at different time points during progression of the disease, celecoxib treatment significantly reduced the incidence and severity of AAAs. The celecoxib treatment also protected the mice from aortic rupture and death. The aneurysmal lesion displayed an altered smooth muscle cell (SMC) phenotype, whereas celecoxib treatment was associated with increased expression of differentiated SMC markers and reduced dedifferentiation marker expression during AAA progression. Maintenance of a differentiated SMC phenotype is associated with the effectiveness of COX-2 inhibition for limiting AAA progression in nonhyperlipidemic mice.

1 Vasorelaxation and hyperpolarization of endothelial cells by adenosine 5 0 -[b-thio]diphosphate (ADPbS) and adenosine 5 0 -[g-thio]triphosphate (ATPgS) were studied in rat-isolated mesenteric artery. Effects from stimulation of P2X receptors were avoided by desensitization with a,b-methylene adenosine triphosphate. 2 ADPbS caused concentration-and endothelium-dependent relaxations of methoxamineprecontracted small (third generation) and main mesenteric artery. These were inhibited by N o -nitro-L-arginine methyl ester (L-NAME) or a combination of apamin plus charybdotoxin (inhibitors of Ca 2+ -activated K + channels); L-NAME, apamin and charybdotoxin applied together abolished the response. 3 ATPgS induced limited relaxation (35% of methoxamine-induced tone at 10 mM) of small mesenteric artery, which was sensitive to L-NAME or endothelium denudation. However, it almost completely relaxed the main mesenteric artery over an extended concentration range (46 orders of magnitude) in an endothelium-dependent manner. This relaxation was inhibited by either L-NAME or a combination of apamin with charybdotoxin, and abolished by a combination of all the three inhibitors. 4 The P2Y 1 receptor antagonist MRS 2179 (2 0 -deoxy-N 6 -methyladenosine 3 0 ,5 0 -bisphosphate; 0.3 -3 mM) caused parallel rightward shifts of the concentration/relaxation curve to ADPbS (pA 2 ¼ 7.1). However, MRS 2179 did not inhibit, but potentiated, relaxant responses to ATPgS. MRS 2179 did not affect the contractile responses ATPgS in small mesenteric artery; ATPgS did not contract the main mesenteric artery. 5 ADPbS hyperpolarized the endothelium of the main mesenteric artery in a concentrationdependent manner. This was unaffected by L-NAME but antagonized by MRS 2179. ATPgS also hyperpolarized the mesenteric artery endothelium in a concentration-dependent manner but, when ATPgS was applied at 10 mM, its effect was potentiated by MRS 2179 (3 mM). 6 It is concluded that both relaxation and hyperpolarization to ADPbS are mediated by P2Y 1 receptors and that the endothelial hyperpolarization is related to the L-NAME-resistant relaxation. Relaxation to the P2Y 2 agonist ATPgS shows regional variation along the mesenteric vasculature. The mechanisms for potentiation of relaxation and hyperpolarization by ATPgS are unknown, but may indicate interactions between P2Y receptor subtypes.

Spinal muscular atrophy is the most common fatal hereditary disease among newborns and infants. There is as yet no effective treatment. Although a carrier test is available, currently there is disagreement among professional medical societies who proffer standards of care as to whether or not carrier screening for spinal muscular atrophy should be offered as part of routine reproductive care. This leaves health care providers without clear guidance. In fall 2009, a meeting was held by National Institutes of Health to examine the scientific basis for spinal muscular atrophy carrier screening and to consider the issues that accompany such screening. In this article, the meeting participants summarize the discussions and conclude that pan-ethnic carrier screening for spinal muscular atrophy is technically feasible and that the specific study of implementing a spinal muscular atrophy carrier screening program raises broader issues about determining the scope and specifics of carrier screening in general.